2. Academic Validation
  3. Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies

Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies

  • Nat Commun. 2017 May 26;8:15424. doi: 10.1038/ncomms15424.
Edurne San José-Enériz 1,  Xabier Agirre 1,  Obdulia Rabal 2,  Amaia Vilas-Zornoza 1,  Juan A Sanchez-Arias 2,  Estibaliz Miranda 1,  Ana Ugarte 2,  Sergio Roa 1,  Bruno Paiva 1,  Ander Estella-Hermoso de Mendoza 2,  Rosa María Alvarez 2,  Noelia Casares 3,  Victor Segura 4,  José I Martín-Subero 5,  François-Xavier Ogi 6,  Pierre Soule 6,  Clara M Santiveri 7,  Ramón Campos-Olivas 7,  Giancarlo Castellano 5,  Maite Garcia Fernandez de Barrena 3,  Juan Roberto Rodriguez-Madoz 1,  Maria José García-Barchino 1,  Juan Jose Lasarte 3,  Matias A Avila 3,  Jose Angel Martinez-Climent 1,  Julen Oyarzabal 2,  Felipe Prosper 1 8
Affiliations

Affiliations

  • 1 Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra, Avenida Pío XII, 55 31008 Pamplona, Spain.
  • 2 Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra, Avenida Pío XII, 55 31008 Pamplona, Spain.
  • 3 Area de Terapia Génica y Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra, Avenida Pío XII, 55 31008 Pamplona, Spain.
  • 4 Unidad de Bioinformática, Centro de Investigación Médica Aplicada, Universidad de Navarra, Avenida Pío XII, 55 31008 Pamplona, Spain.
  • 5 Departamento de Fundamentos Clínicos, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centre Esther Koplowitz, C/ Rosello 153 2nd floor 08036 Barcelona, Spain.
  • 6 Nanotemper Technologies GmbH, Flößergasse 4, Munich, Germany.
  • 7 Spectroscopy and NMR Unit, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3 28029 Madrid, Spain.
  • 8 Departamento de Hematología, Clínica Universidad de Navarra, Universidad de Navarra, Avenida Pío XII, 36 31008 Pamplona, Spain.
PMID: 28548080 DOI: 10.1038/ncomms15424
Abstract

The indisputable role of Epigenetics in Cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes Apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.

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